Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks’ gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. / Methods: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks’ gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. / Findings: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference –3·39%, 90% CI –8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. / Interpretation: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks’ gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. / Funding: UK Medical Research Council and Indian Department of Biotechnology

Misoprostol for primary versus secondary prevention of postpartum haemorrhage: a cluster‐randomised non‐inferiority community trial

OBJECTIVE: To assess whether secondary prevention, which preemptively treats women with above‐average postpartum bleeding, is non‐inferior to universal prophylaxis. DESIGN: A cluster‐randomised non‐inferiority community trial. SETTING: Health sub‐centres and home deliveries in the Bijapur district of Karnataka, India. POPULATION: Women with low‐risk pregnancies who were eligible for delivery with an Auxiliary Nurse Midwife at home or sub‐centre and who consented to be part of the study. METHODS: Auxiliary Nurse Midwifes were randomised to secondary prevention using 800 mcg sublingual misoprostol administered to women with postpartum blood loss ≥350 ml or to universal prophylaxis using 600 mcg oral misoprostol administered to all women during the third stage of labour. MAIN OUTCOME MEASURES: Postpartum haemoglobin ≤7.8 g/dl, mean postpartum blood loss and postpartum haemoglobin, postpartum haemorrhage rate, transfer to higher‐level facilities, acceptability and feasibility of the intervention. RESULTS: Misoprostol was administered to 99.7% of women as primary prevention. In secondary prevention, 92 (4.7%) women had postpartum bleeding ≥350 ml, of which 90 (97.8%) received misoprostol. The proportion of women with postpartum haemoglobin ≤7.8 g/dl was 5.9 and 8.8% in secondary and primary prevention clusters, respectively [difference −2.9%, one‐sided 95% confidence interval (CI) <1.3%]. Postpartum transfer and haemorrhage rates were low (<1%) in both groups. Shivering was more common in primary prevention clusters (P = 0.013). CONCLUSION: Secondary prevention of postpartum haemorrhage with misoprostol is non‐inferior to universal prophylaxis based on the primary outcome of postpartum haemoglobin. Secondary prevention could be a good alternative to universal prophylaxis as it medicates fewer women and is an acceptable and feasible strategy at the community level. TWEETABLE ABSTRACT: Secondary prevention of postpartum haemorrhage with misoprostol is non‐inferior to universal prophylaxis

Pregnancy outcomes and blood pressure visit-to-visit variability and level in three less-developed countries

In pregnancy in well-resourced settings, limited data suggest that higher blood pressure (BP) visit-to-visit variability may be associated with adverse pregnancy outcomes. Included were pregnant women in 22 intervention clusters of the CLIP (Community-Level Interventions for Preeclampsia) cluster randomized trials, who had received at least 2 prenatal contacts from a community health worker, including standardized BP measurement. Mixed-effects adjusted logistic regression assessed relationships between pregnancy outcomes and both BP level (median [interquartile range]) and visit-to-visit variability (SD and average real variability [ARV], adjusted for BP level), among all women and those who became hypertensive. The primary outcome was the CLIP composite of maternal and perinatal mortality and morbidity. Among 17 770 pregnancies, higher systolic and diastolic BP levels were associated with increased odds of the composite outcome per 5 mm Hg increase in BP (odds ratio [OR], 1.05 [95% CI, 1.03–1.07] and OR, 1.08 [1.06–1.11], respectively). Higher BP visit-to-visit variability was associated with increased odds, per a SD increase in BP variability measure, of (1) hypertension (systolic: OR, 2.09 [1.98–2.21] for SD and 1.52 [1.45–1.60] for ARV; diastolic: OR, 2.70 [2.54–2.87] for SD and 1.86 [1.76–1.96] for ARV); and (2) the composite outcome (systolic: OR, 1.10 [1.06–1.14] for SD and 1.06 [1.02–1.10] for ARV; diastolic: OR, 1.07 [1.03–1.11] for SD and 1.06 [1.02–1.09] for ARV). In 3 less-developed countries, higher BP level and visit-to-visit variability predicted adverse pregnancy outcomes, providing an opportunity for high-definition medicine

Evaluation of a novel device for the management of high blood pressure and shock in pregnancy in low-resource settings: Study protocol for a stepped-wedge cluster-randomised controlled trial (CRADLE-3 trial)

© 2018 The Author(s). Background: Obstetric haemorrhage, sepsis and pregnancy hypertension account for more than 50% of maternal deaths worldwide. Early detection and effective management of these conditions relies on vital signs. The Microlife® CRADLE Vital Sign Alert (VSA) is an easy-to-use, accurate device that measures blood pressure and pulse. It incorporates a traffic-light early warning system that alerts all levels of healthcare provider to the need for escalation of care in women with obstetric haemorrhage, sepsis or pregnancy hypertension, thereby aiding early recognition of haemodynamic instability and preventing maternal mortality and morbidity. The aim of the trial was to determine whether implementation of the CRADLE intervention (the Microlife® CRADLE VSA device and CRADLE training package) into routine maternity care in place of existing equipment will reduce a composite outcome of maternal mortality and morbidity in low- and middle-income country populations. Methods: The CRADLE-3 trial was a stepped-wedge cluster-randomised controlled trial of the CRADLE intervention compared to routine maternity care. Each cluster crossed from routine maternity care to the intervention at 2-monthly intervals over the course of 20 months (April 2016 to November 2017). All women identified as pregnant or within 6 weeks postpartum, presenting for maternity care in cluster catchment areas were eligible to participate. Primary outcome data (composite of maternal death, eclampsia and emergency hysterectomy per 10,000 deliveries) were collected at 10 clusters (Gokak, Belgaum, India; Harare, Zimbabwe; Ndola, Zambia; Lusaka, Zambia; Free Town, Sierra Leone; Mbale, Uganda; Kampala, Uganda; Cap Haitien, Haiti; South West, Malawi; Addis Ababa, Ethiopia). This trial was informed by the Medical Research Council guidance for complex interventions. A process evaluation was undertaken to evaluate implementation in each site and a cost-effectiveness evaluation will be undertaken. Discussion: All aspects of this protocol have been evaluated in a feasibility study, with subsequent optimisation of the intervention. This trial will demonstrate the potential impact of the CRADLE intervention on reducing maternal mortality and morbidity in low-resource settings. It is anticipated that the relatively low cost of the intervention and ease of integration into existing health systems will be of significant interest to local, national and international health policy-makers. Trial registration: ISCRTN41244132. Registered on 2 February 2016. Prospective protocol modifications have been recorded and were communicated to the Ethics Committees and Trials Committees. The adapted Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Checklist and the SPIRIT Checklist are attached as Additional file 1